Epigenetic modulation of gene expression is an important mediator of cancer progression. It is well understood that tumor suppressors can be inactivated by the methylation of their promoters, which can contribute to tumor progression. However, select promoters of pro-invasive and pro-metastatic genes can be selectively demethylated, and thus activated, during tumor progression. S100A4 is one such gene that contributes to tumor metastasis in several cancer types and its expression is tightly controlled by promoter methylation. We have found that the integrin ?6?4 can control S100A4 expression in breast cancer by stimulating the demethylation of the S100A4 promoter. Based on our preliminary data and supporting literature, we propose a novel mechanism of producing sncRNAs through transcriptional regulation of antisense RNAs. We postulate that these sncRNAs are generated by double stranded RNAs created through hybridization of sense and antisense transcripts from a given promoter. In the case of the S100A4 promoter, the region that governs the methylation status of the promoter is located in a non-coding alternatively spliced exon. Notably, sncRNAs corresponding to this alternatively spliced exon of S100A4 are present in cells expressing high S100A4, but not in cells lacking S100A4, according to public databases. Furthermore, we provide evidence that integrin ?6?4 controls the expression of an antisense transcript to S100A4. We propose that these sncRNAs then direct methylcytosine modifying enzymes and DNA repair molecules to the site of specific DNA demethylation. Accordingly, the central hypothesis of this application is that integrin ?6?4 stimulates S100A4 promoter demethylation through non-coding RNA-guided modification of methylated cytosines and subsequent DNA mismatch repair. We will test our central hypothesis through completion of the following three aims: 1) Define how integrin ?6?4 directs DNA demethylation of the S100A4 promoter through generation of antisense RNAs and sncRNAs, 2) Determine the involvement of DNA repair in DNA demethylation of the S100A4 promoter, which will aid us in defining the molecules that drive removal of repressive CpG methylation marks, and 3) Define changes in DNA methylation caused by integrin ?6?4 signaling on a genomic scale. If our model is proven largely correct, it will represent a new paradigm of how integrins, non-coding RNAs and RNA processing transmit oncogenic signals. Furthermore, understanding how epigenetic modulation of an invasive and metastatic phenotype is controlled will give us the power to target it therapeutically.